Need for ‘Cut-Off Criteria’ to Prevent the Uncontrolled Spread of Gene Drive Organisms

THIRD WORLD NETWORK BIOSAFETY INFORMATION SERVICE

Dear Friends and Colleagues

Need for ‘Cut-Off Criteria’ to Prevent the Uncontrolled Spread of Gene Drive Organisms

The GeneTip research project was a joint enterprise by the Universities of Bremen and Vechta, the University of Natural Resources and Life Sciences, Vienna and Testbiotech, Munich, carried out from 2017 until 2019. The researchers focused on risks associated with the spread of newly designed genetically engineered (GE) organisms into the environment particularly those derived using gene drives (Item 1). The results have now been published in full in a book titled “Gene Drives at Tipping Points“ (https://link.springer.com/book/10.1007/978-3-030-38934-5).

Gene drives are designed to spread GE organisms rapidly through natural populations to suppress or eradicate the target species within a region, or to replace it with GE populations. Gene drive organisms are designed to persist and propagate in the environment within natural populations, potentially over an unlimited period of time. GeneTip has shown that the technical and biological characteristics of the organisms, including their ability to persist and become invasive, are decisive for the dynamics of the targeted populations and their potential for gene flow to other species. In addition, there may be distinct interactions with the environment and the ecosystems in which the organisms propagate and spread. Once started, the spread can no longer be effectively controlled, and it can be further expected that unintended characteristics can emerge in following generations.

The European Food Safety Authority (EFSA) is currently working on guidance for the risk assessment of mosquitoes which inherit GE gene drives. There are proposals to use these mosquitoes to fight malaria in Africa. Testbiotech has published a peer-reviewed paper showing that this poses a substantial problem in risk assessment and that the outcome of any release of GE mosquitoes can massively deviate from what was originally expected (Items 2 and 3). There is no sufficiently reliable method to predict the biological effects in the offspring of the GE mosquitoes. The risks include a higher risk of disease transmission, triggering allergenic reactions due to mosquito bites or severe disruption in ecosystems.

To control the risks of gene drives, ‘cut-off criteria’ need to be defined to prevent the uncontrolled spread of GE organisms (Item 3). Testbiotech suggests three criteria to be taken into account: the biology of the target, their naturally occurring interactions with the environment (biotic and abiotic) and their intended biological characteristics introduced by genetic engineering. These three criteria will merge to form an additional step in environmental risk assessment with the aim of assessing the spatio-temporal controllability of GE gene drive organisms which can then be used to define ‘cut-off criteria’ in the risk analysis of GE gene drive organisms. If gene drive organisms cannot be controlled in space and time, then risk assessment cannot come to sufficiently reliable conclusions. Releases cannot be allowed under such conditions pursuant to the precautionary principle. This recommendation by Testbiotech is also based on the results of the GeneTip research project.

27 April 2020 / The GeneTip research project was a joint enterprise carried out from 2017 until 2019 by the Universities of Bremen and Vechta, the University of Natural Resources and Life Sciences, Vienna and Testbiotech, Munich. The researchers focused on risks associated with the spread of newly designed genetically engineered organisms into the environment. In particular, the project examined plants and animals with a so-called gene drive. The results have now been published in full by the Springer Publishing Company in a book titled “Gene Drives at Tipping Points“ (open access).

The project was funded by the German Federal Ministry of Education and Research (BMBF) and coordinated by the University of Bremen (project code 01LC1724). The published results give a detailed overview of the technical characteristics of gene drives as well as associated risks.

Gene drives are designed to spread genetically engineered organisms rapidly through natural populations. In populations with sexual reproduction, genetic characteristics are normally distributed with a 50% probability to the offspring. The gene drive mechanism, however, interferes with process of natural inheritance, aiming to pass on new genetic information to almost 100% of following generations. There are ongoing debates about using gene drives to combat insects such as mosquitoes and fruit flies, or rodents such as mice and rats. The aim is to suppress or eradicate the target species within a region, or to replace it with genetically engineered populations.

So far, in most cases, the aim has been to prevent as far as possible the spread of genetically engineered organisms. However, gene drive organisms are designed to persist and propagate in the environment within natural populations, potentially over an unlimited period of time. Furthermore, it has to be expected that unintended characteristics can emerge in following generations. In addition, a high degree of exposure means there needs to be a presumption of unforeseeable interactions with ecosystems. Therefore, comprehensive prospective technology characterisation and assessment of associated risks are vital.

GeneTip has shown that the technical and biological characteristics of the organisms, including their ability to persist and become invasive, are decisive for the dynamics of the targeted populations and their potential for gene flow to other species. In addition, there may be distinct interactions with the environment and the ecosystems in which the organisms propagate and spread.

The GeneTip results show that reasonable scientific concerns can be identified at an early stage of the technical developments. Uncertainties and limits of knowledge are high hurdles in regard to the precautionary principle, which can make it necessary to limit or prevent environmental releases.

30 April 2020 / The European Food Safety Authority (EFSA) carried out a public consultation on guidance for the risk assessment of so-called gene drives at the request of the EU Commission. At the same time, a new Testbiotech scientific paper was accepted after peer review. The paper shows that the EFSA concept is insufficient. To control the risks of gene drives, ‘cut-off criteria’ need to be defined to prevent the uncontrolled spread of genetically engineered organisms.

Gene drives are genetic elements which can spread much more widely than would normally be expected. In recent years, artificial gene constructs have been developed using the gene scissor CRISPR/Cas. Organisms, inheriting such gene constructs, are meant to be released and intended to spread rapidly, especially throughout wild populations. The goal is to replace or eradicate the targeted species. However, once started, the spread can no longer be effectively controlled. Damage to human health and the environment can be extensive.

Against this backdrop, EFSA is currently working on guidance for the risk assessment of mosquitoes which inherit genetically engineered gene drives. There are already proposals to use these mosquitoes to fight malaria in Africa: the plan is to eradicate those species which can transmit malaria via a mutagenic chain reaction, or replace them with mosquitoes that can no longer be a vector of the disease.

As the new Testbiotech publication shows, this poses a substantial problem in risk assessment: to be successful, the genetic construct has to be inherited by dozens of generations and billions of mosquitoes. This process would take place in the natural environment outside of the laboratories, over longer periods of time, without effective control mechanisms being available. During this process, the genetically engineered mosquitoes and their offspring would be exposed to an unlimited number of genetic factors and environmental impacts. Therefore, the outcome of any release of genetically engineered mosquitoes can massively deviate from what was originally expected.

There is no sufficiently reliable method to predict the biological effects in the offspring of the genetically engineered mosquitoes. The risks include a higher risk of disease transmission, triggering allergenic reactions due to mosquito bites or severe disruption in ecosystems.

These risks are indeed acknowledged in the text provided by EFSA for the public consultation. However, EFSA does not mention that the precautionary principle must be applied: the EU only allows the release of genetically engineered organisms if they have been demonstrated to be safe, and if they can be retrieved from the environment where an urgent need arises. Neither of these conditions are met in the case of genetically engineered gene drive mosquitoes. Against this backdrop, Testbiotech is demanding substantial amendments to the EFSA draft.

If gene drive organisms cannot be controlled in space and time, then risk assessment cannot come to sufficiently reliable conclusions. Releases cannot be allowed under such conditions. The Testbiotech recommendation is further based on the results of the GeneTip research project which published its final findings this week.

Gene drive organisms are a recent development created by using methods of genetic engineering; they inherit genetic constructs that are passed on to future generations with a higher probability than with Mendelian inheritance. There are some specific challenges inherent to the environmental risk assessment (ERA) of genetically engineered (GE) gene drive organisms, since subsequent generations of these GE organisms might show effects that were not observed or intended in the former generations. Unintended effects can emerge from interaction of the gene drive construct with the heterogeneous genetic background of natural populations and/or be triggered by changing environmental conditions. This is especially relevant in case of gene drives with invasive characteristics and typically takes dozens of generations to render the desired effect. Under these circumstances, ‘next generation effects’ can substantially increase the spatial and temporal complexity associated with a high level of uncertainty in ERA. To deal with these problems, we suggest the introduction of a new additional step in the ERA of GE gene drive organisms that takes three criteria into account: the biology of the target, their naturally occurring interactions with the environment (biotic and abiotic) and their intended biological characteristics introduced by genetic engineering. These three criteria are merged to form an additional step in ERA, combining specific ‘knowns’ and integrating areas of ‘known unknowns’ and uncertainties, with the aim of assessing the spatio-temporal controllability of GE gene drive organisms. The establishment of assessing spatio-temporal controllability can be used to define so-called ‘cut-off’ criteria in the risk analysis of GE gene drive organisms: if it is likely that GE gene drive organisms escape spatio-temporal controllability, the risk assessment cannot be sufficiently reliable because it is not conclusive. Under such circumstances, the environmental release of the GE gene drive organisms would not be compatible with the precautionary principle.